In traumatic brain injury (TBI), adenosine activates high affinity A1 receptors conferring anti-excitotoxic effects. After TBI, however, adenosine levels are high-activating lower affinity A2a receptors that may down-regulate A1 and confer direct neurotoxicity. In models of Parkinson's disease, A2a receptor antagonists are neuroprotective. We reported neuroprotective effects of adenosine after TBI-via anti-excitotoxic effects at the A1 receptor. However, activation of lower affinity A2a receptors could negate this benefit. Out pilot studies show that A2a receptor ko mice are neuroprotected vs wt after experimental TBI and administration of the A2a agonist CGS21680 worsens outcome. However, A2a receptor agonists increase cerebral blood flow (CBF), a finding that must be reconciled. Our clinical studies show that increases in adenosine in cerebrospinal fluid (CSF) are associated with poor outcome. A therapeutic opportunity for A2a receptor antagonists is suggested; however, this pathway must be first studied in experimental TBI. A2a receptor signal transduction is coupled to adenyl cyclase (AC). We reported progressive increases in cAMP levels in CSF after clinical TBI. Hypothesis: Treatment with A2a receptor antagonists or inactivation of the A2a receptor will improve outcome after experimental TBI. Using the controlled cortical impact (CCI) model of TBI in mice and rats, we will address five aims: (1) Determine A2a receptor dynamics after CCI in mice and rats, (2) Assess the role of the A2a receptor in determining biochemical (glutamate, ACh, cAMP), functional, and histological outcome after CCI in mice and rats, including A2a receptor ko mice, (3) Assess the effects of A2a receptor activation on CBF and cerebral metabolic rate after CCI in rats. (4) Define the role of A2a receptor-mediated activation of AC after CCI in mice and rats, (5) Determine the role of the A1 receptor in the detrimental effects of A2a agonists in CCI using A1 receptor ko mice, and (6) To bridge bench and bedside after severe TBI in humans, using CSF samples from 161 patients, we will quantify levels of the non-selective adenosine receptor antagonist caffeine (and metabolites) to test the hypothesis that acute caffeine consumption is associated with favorable outcome and reduced cAMP. These studies explore the most promising adenosine-based therapy for TBI-A2a receptor antagonists. Our bench to bedside track record ensures translation to the clinic. [unreadable] [unreadable]